Jianjun Zhang

Bone defect repair is a precisely choreographed, multiphase cascade that imposes temporally distinct demands on the implanted scaffold. The critical challenge is to create an implant that sustains potent anti-inflammatory and osteogenic signals while eroding at a pace matched to the more than 6-month remodeling timeline. Here, we reported ultralong-acting microspheres that meet this requirement across the entire regeneration program. By synergistically integrating polydopamine-coated poly(lactic-co-glycolic acid) (PLGA–PDA) microspheres with nanohydroxyapatite (nHAP) and mesenchymal stem cell-derived exosomes (Exo), the nHAP/PLGA–PDA@Exo system reconciled extended degradation with durable bioactivity. nHAP neutralized acidic PLGA byproducts to decelerate matrix erosion and release calcium ions, amplifing osteoinduction. Exo modulated inflammation, promoted angiogenesis, and enhanced tissue regeneration, while the PDA coating maximized Exo loading and orchestrated its sustained release. The microspheres released bioactive Exo for more than 3 weeks and retained mechanical integrity for over 6 weeks, thereby furnishing continuous immunomodulation, robust osteogenesis, and time-matched structural support. By dynamically coordinating immune modulation and bone formation throughout the inflammatory, reparative, and remodeling phases, nHAP/PLGA–PDA@Exo offered a clinically translatable strategy for bone defects.

Oral squamous cell carcinoma is one of the most common types of cancer. Surgical resection is one of the most important treatments at present. However, patients often suffer from regional recurrence after surgery. Therefore, new strategies for combination therapy need to be investigated. This work identified a smart injectable hydrogel system co-delivering DOX and sunitinib nanoparticles. The nano drugs are continuously released from the hydrogels and effectively taken up by cells. The nano drugs in the hydrogel can inhibit tumor cell viability and induce cancer cell apoptosis in vitro. The drug-loaded hydrogel could control the recurrence of subcutaneous xenograft tumors, prolong the survival time, and have no obvious toxicity in nude mice. These findings suggest that this smart injectable hydrogel system may provide new ideas for the comprehensive treatment of oral squamous cell carcinoma.

Background: Corneal neovascularization (CoNV) threatens vision by disrupting corneal avascularity, however, current treatments, including pharmacotherapy and surgery, are hindered by limitations in efficacy and adverse effects. Minocycline, known for its anti-inflammatory properties, could suppress CoNV but faces challenges in effective delivery due to the cornea's unique structure. Therefore, in this study a novel drug delivery system using minocycline-loaded nano-hydroxyapatite/poly (lactic-co-glycolic acid) (nHAP/PLGA) nanoparticles was developed to improve treatment outcomes for CoNV. Results: Ultra-small nHAP was synthesized using high gravity technology, then encapsulated in PLGA by a double emulsion method to form nHAP/PLGA microspheres, attenuating the acidic by-products of PLGA degradation. The MINO@PLGA nanocomplex, featuring sustained release and permeation properties, demonstrated an efficient delivery system for minocycline that significantly inhibited the CoNV area in an alkali-burn model without exhibiting apparent cytotoxicity. On day 14, the in vivo microscope examination and ex vivo CD31 staining corroborated the inhibition of neovascularization, with the significantly smaller CoNV area (29.40% ± 6.55%) in the MINO@PLGA Tid group (three times daily) than that of the control group (86.81% ± 15.71%), the MINO group (72.42% ± 30.15%), and the PLGA group (86.87% ± 14.94%) (p < 0.05). Fluorescein sodium staining show MINO@PLGA treatments, administered once daily (Qd) and three times daily (Tid) demonstrated rapid corneal epithelial healing while the Alkali injury group and the DEX group showed longer healing times (p < 0.05). Additionally, compared to the control group, treatments with dexamethasone, MINO, and MINO@PLGA were associated with an increased expression of TGF-β as evidenced by immunofluorescence, while the levels of pro-inflammatory cytokines IL-1β and TNF-α demonstrated a significant decrease following alkali burn. Safety evaluations, including assessments of renal and hepatic biomarkers, along with H&E staining of major organs, revealed no significant cytotoxicity of the MINO@PLGA nanocomplex in vivo. Conclusions: The novel MINO@PLGA nanocomplex, comprising minocycline-loaded nHAP/PLGA microspheres, has shown a substantial capacity for preventing CoNV. This study confirms the complex's ability to downregulate inflammatory pathways, significantly reducing CoNV with minimal cytotoxicity and high biosafety in vivo. Given these findings, MINO@PLGA stands as a highly promising candidate for ocular conditions characterized by CoNV. Graphical

GSK2606414 is a new, effective, highly selective PERK inhibitor with adenosine-triphosphate-competitive characteristics. It can inhibit endoplasmic reticulum stress and has the possibility of treating periodontitis. However, owing to its strong hydrophobicity and side effects, highly efficient pharmaceutical formulations are urgently needed to improve the bioavailability and therapeutic efficacy of GSK2606414 in the treatment of periodontitis. Herein, a novel local GSK2606414 delivery system was developed by synthesizing GSK2606414 nanoparticles (NanoGSK) and further loading NanoGSK into a collagenase-responsive hydrogel. The drug release results showed that the drug-loaded hydrogels had outstanding enzymatic responsive drug release profiles under the local microenvironment of periodontitis. Furthermore, in vitro studies showed that the drug-loaded hydrogel exhibited good cellular uptake and did not affect the growth and proliferation of normal cells, while the drug-loaded hydrogel significantly improved the osteogenic differentiation of inflammatory cells. In the evaluations of periodontal tissue repair, the drug-loaded hydrogels showed a great effect on inflammation inhibition, as well as alveolar bone regeneration. Therefore, this work introduces a promising strategy for the clinical treatment of periodontitis.

GMSCs-Exo promote proliferation, migration, and tube formation of HUVECs by regulating the Wnt/β-catenin signalling pathway in a high-glucose environment. GMSCs-Exo were loaded and delivered via PHE microspheres, novel porous microscaffolds with superb biocompatibility.

Breast cancer is one of the most common types of cancer. Patients are often concerned about regional recurrence after breast cancer surgery. Radiotherapy plays a vital role in reducing recurrence and prolonging the survival of patients undergoing breast-conserving surgery and high-risk mastectomy. However, 8–15% of patients still have disease progression due to radiation resistance. Therefore, new strategies for combination radiotherapy sensitization must be investigated. In this study, an implantable drug loading system, sunitinib nanoparticles @ matrix metalloproteinases -response hydrogel (NSMRH), uses enzyme-sensitive hydrogel as a carrier to load sunitinib nanoparticles, was identified. The releasing profile demonstrated that sunitinib nanoparticles may be continuously released from the hydrogels. Functional experiments revealed that, when paired with NSMRH, radiation may significantly inhibit tumor cell proliferation, migration, and invasion in vitro. Further animal experiments showed that NSMRH combined with radiotherapy could more effectively control the recurrence of subcutaneous xenograft tumors, prolong the survival time, and have no obvious toxicity in nude mice. Finally, by studying the molecular mechanism of NSMRH, it was hypothesized that in breast cancer cells, NSMRH cooperated with sensitized radiotherapy, mainly due to significantly blocking the G2/M phase, reducing the DNA repair efficiency, inhibiting tumor angiogenesis, promoting apoptosis, and reversing the abnormal expression of platelet-derived growth factor receptor alpha (PDGFRA) after radiotherapy. These findings suggest that NSMRH’s radiation sensitization and anti-tumor activity may aid in the development of a novel method in future clinical applications.